Relationship between oxidative stress, varicocele and infertility: A meta-analysis
Open accessAbstract
Varicocele is one of the leading causes of male infertility, and is present in almost 40% of infertile males. Recent understanding of the role of oxidative stress in male reproduction has led some researchers to postulate oxidative stress as the possible cause of sperm dysfunction in varicocele patients. The objective of the present study was to examine the published literature on the role of oxidative stress in patients with varicocele as the aetiology of their infertility. Twenty-three human studies were identified after an extensive search dealing with the role of oxidative stress in varicocele-associated infertility. Out of these studies, four were selected that measured similar types of reactive oxygen species (ROS) by a similar method of measurement. The data were then entered in the RevMan software for analysis. The overall estimate showed that patients have significantly higher concentrations of ROS than controls, with the mean difference being 0.73 (95% CI 0.40, 1.06, P < 0.0001). This translated to an ROS concentration of 4.37 x 10(4) cpm/20 x 10(6) spermatozoa/ml on the linear scale. Total antioxidant capacity levels were found to be significantly lower in the infertile varicocele patients, with 386 fewer trolox equivalents than the controls (95% CI -556.56-216.96, P < 0.00001). From the results, it can be concluded that there is increased oxidative stress in varicocele patients; however, more studies are needed to confirm this finding.
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Seminal OS develops due to production of excessive amounts of ROS in numerous medical conditions, including varicocele, leukocytospermia, diabetes mellitus, and obesity.
“Due to the production of excessive amounts of ROS in numerous medical conditions, including varicocele [43], leukocytospermia [44], diabetes mellitus [45], and obesity [46], seminal OS develops.”
From The Sixth Edition of the WHO Manual for Human Semen Analysis: A Critical Review and SWOT Analysis (2021) · cites this paper as [43]
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Research works printed but not linked: 8
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Gosálvez, J., Rodríguez-Predreira, M., Mosquera, A., López-Fernández, C., Esteves, S. C., Agarwal, A., & Fernández, J. (2014) · Andrologia · doi:10.1111/and.12118 · Cited by 34 · see citing works
Self-citationSeminal plasma total antioxidant capacity and semen parameters in patients with varicocele.
Giulini, S., Sblendorio, V., Xella, S., Marca, A. L., Palmieri, B., & Volpe, A. (2009) · Reproductive Biomedicine Online · doi:10.1016/s1472-6483(10)60004-1 · Cited by 34
The most important medicinal plants affecting sperm and testosterone production: a systematic review
Boroujeni, S. N., Malamiri, F. A., Bossaghzadeh, F., Esmaeili, A., & Moudi, E. (2022) · JBRA Assisted Reproduction · doi:10.5935/1518-0557.20210108 · Cited by 33
“According to several studies, oxidative stress can cause molecular and genetic defects causing infertility (Agarwal et al., 2006).”
BackgroundPoli, G., Fabi, C., Sugoni, C., Bellet, M., Costantini, C., Luca, G., & Brancorsini, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095233 · Cited by 32
“Indeed, Agarwal and colleagues identify a significantly lower total of antioxidant capacity levels in the semen of infertile VC patients, associated with elevated ROS levels, in a meta-analysis study [78].”
BackgroundReactive Oxygen Species (ROS) level in seminal plasma of infertile men and healthy donors
Moein, M., Dehghani, V., Tabibnejad, N., & Vahidi, S. (2009) · doi:10.1016/j.urology.2009.07.266 · Cited by 32
“incidence of varicocele is about 40% in infertile men (15) which is lower than this percentage in the present study (79.”
BackgroundResultMitochondria-Targeted Compounds to Assess and Improve Human Sperm Function
Escada‐Rebelo, S., Cristo, M. I., Ramalho‐Santos, J., & Amaral, S. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0238 · Cited by 39 · see citing works
“…these seminal sources, varicocele (abnormal dilatation of the scrotal veins) is also considered an endogenous source, as it has been shown that the level of seminal ROS is proportional to the varicocele grade (277), and patients with varicocele exhibit higher OS and lowered antioxidant levels (11).”
Zhu, X.-Y., Yu, C.-X., Wu, W.-L., Shi, L., Jiang, C.-Y., Wang, L., Ding, Z.-D., & Liu, Y. (2021) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-022-00893-7 · Cited by 31 · see citing works
“As an etiological factor, excessive reactive oxygen species (ROS) generation imposes an oxidative stress that contributes to between 30 and 80% of cases of male infertility [4, 5].”
BackgroundSperm DNA Integrity Test and Assisted Reproductive Technology (Art) Outcome
Rilcheva, V., Ayvazova, N., Ilieva, L. O., Ivanova, S., & Konova, E. (2016) · doi:10.1515/jbcr-2016-0003 · Cited by 31
Mysteries, Facts, and Fiction in Varicocele Pathophysiology and Treatment
Sofikitis, N., Stavrou, S., Skouros, S., Dimitriadis, F., Tsounapi, P., & Takenaka, A. (2014) · doi:10.1016/j.eursup.2014.07.002 · Cited by 31
“A meta-analysis by Agarwal and coworkers [60] also suggested that reduced total antioxidant capacity and increased oxidative stress may be a component in the etiology of infertility in men with varicocele.”
BackgroundInfluence of Seminal Plasma Antioxidants and Osteopontin on Fertility of the Arabian Horse
Waheed, M., El-Bahr, S., & Alhaider, A. (2013) · doi:10.1016/j.jevs.2012.11.006 · Cited by 31
Kaltsas, A., Dimitriadis, F., Zachariou, D., Zikopoulos, A., Symeonidis, E. N., Markou, E., Tien, D. M. B., Takenaka, A., Sofikitis, N., & Zachariou, A. (2023) · Medicina · doi:10.3390/medicina59101835 · Cited by 32 · see citing works
“When these surgical procedures are paired with IVF or ICSI, clinical pregnancy rates can be as high as 65%, with sperm recovery rates potentially reaching 100% [106,110].”
BackgroundMethodEl-Domyati, M., Al-Din, A.-B. M., Barakat, M. T., El-Fakahany, H., Honig, S., Xu, J.-S., & Sakkas, D. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.10.031 · Cited by 29
Lira, F., Campos, L., Roque, M., & Esteves, S. C. (2024) · International Brazilian Journal of Urology · doi:10.1590/s1677-5538.ibju.2024.9917 · Cited by 28
1H NMR-based metabonomics for infertility diagnosis in men with varicocele
Lira, F., Marques, R. A., Cavalcanti, A. D. F., Araújo, L. C. N., Lima, S., Pinto, L., & Silva, R. (2020) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-020-01896-2 · Cited by 28
“There are studies that have demonstrated increased seminal concentration of ROS as well as end products of oxidative stress when men with varicocele were compared with fertile men [29].”
BackgroundAzoospermia factor deletions in varicocele cases with severe oligozoospermia.
Dada, R., Kumar, R., Shamsi, M. B., Sidhu, T., Mitra, A., Singh, S., Sharma, R., Gupta, S., & Gupta, N. (2007) · Indian Journal of Medical Sciences · doi:10.4103/0019-5359.34519 · Cited by 28
Irigoyen, P., Pintos-Polasky, P., Rosa-Villagrán, L., Skowronek, M., Cassina, A., & Sapiro, R. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.926684 · Cited by 27 · see citing works
“There are already several essays available for measuring antioxidant capacity (Zini et al., 2000; Agarwal and Prabakaran, 2005; Baker and Aitken, 2005; Agarwal et al., 2006; Khosrowbeygi and Zarghami, 2007; Agarwal et al., 2015; Sharma et al., 2017; Robert et al., 2020).”
BackgroundOxidative stress in human reproduction: Shedding light on a complicated Phenomenon
Agarwal, A., Sharma, R., Gupta, S., Harlev, A., Ahmad, G., du Plessis, S., Esteves, S., Wang, S., & Durairajanayagam, D. (2017) · doi:10.1007/978-3-319-48427-3 · Cited by 26
Self-citationTsili, A., Xiropotamou, O. N., Sylakos, A., Maliakas, V., Sofikitis, N., & Argyropoulou, M. (2017) · World Journal of Radiology · doi:10.4329/wjr.v9.i2.34 · Cited by 25
García-Peiró, A., Oliver-Bonet, M., Navarro, J., Abad, C., Amengual, M., López-Fernández, C., Gosálvez, J., & Benet, J. (2012) · Journal of Andrology · doi:10.2164/jandrol.111.013722 · Cited by 25
“This could be the most parsimonious explanation for the high frequency of DDS observed in varicocele patients, where the level of reactive oxygen species exposure is extremely high (Allamaneni et al, 2004; Mancini et al, 2004; Agarwal et al, 2006; Mostafa et al, 2006; Pasqualotto et al, 2008).”
BackgroundKim, S.-Y., Lim, J. W., Kim, J., Park, S. Y., & Seo, J. (2015) · Systems Biology in Reproductive Medicine · doi:10.3109/19396368.2015.1049752 · Cited by 24
“MTHFR, MTR, and MTRR play an important role in folate metabolism, and Hcy levels could affect DNA synthesis and methylation, leading to increased oxidative stress [Agarwal et al. 2006] and disrupted methylation [Frosst et al.”
BackgroundClinical utility of sperm DNA damage in male infertility
Majzoub, A. A., Agarwal, A. K., & Esteves, S. C. (2019) · Panminerva Medica · doi:10.23736/s0031-0808.18.03530-9 · Cited by 29 · see citing works
Self-citationAsadi, N., Kheradmand, A., Gholami, M., & Moradi, F. (2018) · Andrologia · doi:10.1111/and.13106 · Cited by 23
The epigenetic approach of varicocele: a focus on sperm DNA and m6A-RNA methylation
Naderi, N., Tavalaee, M., & Nasr‐Esfahani, M. H. (2024) · Human Reproduction Update · doi:10.1093/humupd/dmae034 · Cited by 19 · see citing works
Evaluation of seminal plasma HSPA2 protein as a biomarker of human spermatogenesis status.
Nowicka-Bauer, K., Malcher, A., Włoczkowska, O., Kamieniczna, M., Olszewska, M., & Kurpisz, M. (2021) · Reproductive Biology · doi:10.1016/j.repbio.2021.100597 · Cited by 20
Male Infertility: Pathogenetic Significance of Oxidative Stress and Antioxidant Defence (Review)
Koshevoy, V., Naumenko, S., Skliarov, P., Fedorenko, S., & Kostyshyn, L. (2021) · Scientific Horizons · doi:10.48077/scihor.24(6).2021.107-116 · Cited by 20 · see citing works
- Authors
- Agarwal, A., Prabakaran, S., & Allamaneni, S. S.
- Affiliations
- Glickman Urological Institute (US)
- Venue
- Reproductive BioMedicine Online
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 12
- Issue
- 5
- Pages
- 630-633
- ISSN
- 1472-6483 (ISSN-L)
- OpenAlex
- W2169474580
- Cited by
- 261
- References
- 20
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 15 · 2023: 20 · 2022: 22 · 2021: 20 · 2020: 19 · 2019: 11 · 2018: 9 · 2017: 17 · 2016: 9 · 2015: 18 · 2014: 8 · 2013: 13 · 2012: 18
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Reproductive BioMedicine Online (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cleveland Clinic
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Health Professions › General Health Professions › Male Reproductive Health Studies
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- varicocele, male infertility, oxidative stress, reactive oxygen species, sperm dysfunction, total antioxidant capacity, antioxidant status
- MeSH terms
- Antioxidants, Humans, Infertility, Male, Male, Spermatozoa, Varicocele, Reactive Oxygen Species, Oxidative Stress
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